Both the pathogenesis and etiology of Alzheimer's disease are unknown. Severity of the disease is correlate with deficits of cholinergic functions in the cortex and hippocampus accompanied by the loss of cholinergic neurons in the basal forebrain which innervate these regions. This neuronal loss may be a consequence of changes in biochemical signals coming from the cells which these neurons innervate of from surrounding non-neuronal cells. The long-term objective of this research is to identify endogenous compounds in the brain which can enhance the survival, growth and differentiation of cholinergic neurons in the basal forebrain, to characterize their modes of action and to establish their physiological relevance. Such information may help to elucidate the etiology of the cholinergic deficit in Alzheimer's disease and lead to the development of a useful therapy. Our studies have already led to the finding that phosphoethanol-amine can enhance the synthesis of acetylcholine forebrain cholinergic neurons. The specific aims of this project are as follows: (1) to determine the specificity of action of phosphoethanolamine on different neuronal populations by examining its in vitro effects on neurotransmitter synthesis and uptake in cholinergic, dopaminergic and GABAergic neurons: (2) to determine if phosphoethanolamine enhances acetylcholine synthesis by influencing the survival of cholinergic neurons, or by modulating the transport and metabolism of choline: (3) to determine if phosphoethanolamine can increase the in vivo synthesis and release of acetylcholine in aged rat brains and in lesioned adult brains which have received embryonic transplants. Specific aim (1) and (2) will be addressed by measuring biochemical changes in neurotransmitter enzyme activities , uptake processes, and the synthesis and release of neurotransmitter in cultured cells and tissue preparations. Immunohistochemical techniques will also be employed to monitor survival effects. Specific aim (3) will be investigated by infusing phosphoethanolamine into rat brains and measuring subsequent effects on acetylcholine synthesis and release by in vivo brain microdialysis or by biochemical and histochemical measurements on brain slices.